A patch for transdermal cannabinoid delivery could be therapeutically important in the reduction of chronic pain, especially for patients who can't get pain relief from traditional treatments. Addition of a cannabinoid patch to a patient's standard pain-relief regimen could enhance analgesia because this class of drugs works by a different antinociceptive mechanism. Release of endocannabinoids (eCBs), such as anandamide (AEA), occurs in response to injury to relieve pain and inflammation. Inhibitors of eCB degradation mechanisms and transporters, such as AM404, have been developed to induce and prolong the effects of the eCBs in situations of injury-induced pain and inflammation. Endocannabinoid and inhibitor compounds are clinically interesting because they initiate therapeutic effects via cannabinoid (CB) receptors without producing the side effects common to traditional cannabinoid agonist compounds, such as THC. N-(4- hydroxyphenyl) arachidonoylamide (AM404) has been shown to relieve neuropathic pain and reduce alcohol consumption and anxiety in animals. N-arachidonoyl dopamine (NADA) is an eCB that acts at the CB receptor 1 which is associated with pain and emesis reduction. Transdermal delivery has numerous advantages over other drug delivery methods such as bypassing first-pass metabolism, extended controlled drug release, and the added ability for patients to self-administer the drug pain-free. NADA and AM404 present a challenge for transdermal delivery because of their high lipophilicity and enzymatic/chemical instability. The goal of this project is to improve the transdermal delivery of the hydroxyphenylarachidonylamides NADA and AM404. We propose to synthesize hydrophilic prodrugs of these compounds to promote their delivery across the skin barrier and possibly increase their stability. The additional phenolic hydroxyl in NADA will allow us to evaluate the effect of disubstituted prodrugs, as compared to monosubstituted prodrugs of the AM404 structure. The proposed hydrophilic prodrugs will be useful in investigating quantitative-structure-permeability relationships (QSPR) of transdermal flux used to develop and improve delivery strategies for highly lipophilic compounds. The specific aims for this project are: (1) to study the diffusion and metabolism of NADA and AM404 across the skin barrier (2) to synthesize a series of prodrugs for transdermal flux optimization (3) to measure the penetration/concurrent bioconversion of the prodrugs through human skin in vitro and (4) to characterize the pharmacokinetics of the drugs in guinea pigs in vivo. Correlation of our in vitro data with the in vivo model will aid in developing a QSPR database for transdermal prodrugs.